Erythropoietin (EPO) is an effective therapy for anemia of end-stage renal disease (ESRD) and is used in almost all ESRD patients receiving chronic hemodialysis. EPO stimulated iron utilization, coupled with small but unavoidable loss of extra corporeal blood with hemodialysis, leads to iron deficiency in almost all patients. Adequate iron delivery, by oral or parenteral supplementation, is necessary for optimal EPO action. Compliance with oral iron is poor due to gastrointestinal toxicity. Therefore intravenous (i.v.) iron is administered to 50-75 percent of hemodialysis patients, either intermittently when iron deficiency develops or at regular intervals to prevent iron depletion. Parenteral iron is a pro-oxidant, and may increase the risk of infections, inflammation and atherosclerosis by further enhancing oxidative stress and inflammation present in the majority of hemodialysis patients. Unlike the large polymeric iron complexes that are administered i.v., ferric pyrophosphate (FePPi), a monomeric iron salt (745 Da), can be delivered directly into the circulation when added to dialysis solutions. Fe(III) complexes tightly with pyrophosphate (PPi), thereby reducing dissociation and release of free iron. PPi anion is an antioxidant that promotes direct delivery of iron to transferrin, and iron transfer from transferrin to ferritin. FePPi is highly soluble in the acid concentrate and a concentrate fortified with FePPi can be used to generate a dialysate with defmed concentration of FePPi (Fe-HD). This is a double-blinded, randomized, controlled Phase II clinical trial to determine the safety and efficacy of FePPi added to the hemodialysis solutions in ESRD patients over a period of 9 months. Iron replete patients in=30) with no evidence of iron overload (transferrin saturation or TSAT< 40 percent, and ferritin < 800 lag/L), who have needed intravenous iron in the previous 2 months will be enrolled. Patients will be randomized to receive hemodialysis using Fe-HD or C-HD with every dialysis session for a total period of 9 months. The initial dose of dialysate iron will be 9 lag/dl if TSAT is 30-40 percent, and 11 lag/dl if TSAT is < 30 percent. Serum iron parameters (TSAT and ferritin) will be monitored every month. The dialysate iron concentration will be reduced to 9 lag/dl if pre-dialysis TSAT increases to 35-40 percent, and dialysate iron will be held if TSAT exceeds 40 percent. Dialysate iron will be restarted at 11 lag/dl if TSAT is < 30 percent and at 9 lag/dl if TSAT is 30-40 percent. Patients in both groups will receive 500 mg i.v. iron saccharate (Venofer(r)) in 5 divided doses at 5 consecutive dialysis sessions if TSAT is < 20 percent. Patients in the dialysate iron group will continue to receive dialysate iron even if they require a course of i.v. iron. The dose of EPO will be adjusted every 6 weeks, according to a protocol, with the goal of maintaining hemoglobin between 11 to 12 grn/dl. Safety parameters will be carefully monitored throughout the trial. The primary end-points will be the development of iron deficiency (TSAT< 20 percent) that necessitates intravenous iron therapy and the amount of i.v. iron needed by the patients in the two groups. A secondary end-point will be development of iron overload (TSAT> 40 percent and ferritin > 800 lag/L). The acute and chronic effects of dialysate iron on serum levels of catalytically active iron and markers of inflammation and oxidative stress will be measured at the beginning and the end of the study. This Phase II study will provide preliminary evidence of the safety and efficacy of ferric pyrophosphate infusion via the dialysate, with the aim of preventing iron deficiency, and pave the way for a large, clinical trial of dialysate iron therapy.